Compound (I), disclosed for the first time in WO 01/02407, is particularly active against breast, lung, ovary, colon, prostate, kidney and pancreas tumours, also in case of resistance to known antitumour agents such as adriamycin, vinblastine and some Pt derivatives.
A number of synthetic methods for the preparation of (I), which comprise the use of an oxazolidine-protected side chain, are reported in the literature. In U.S. Pat. No. 6,737,534 10-deacetylbaccatin III, a starting material easily available from Taxus baccata leaves, is first protected at the 7- and 10-positions, oxidised at the 13-position and then hydroxylated at the 14-position. Thereafter, carbonation of the vicinal-1,14 hydroxy groups to give the 1,14-carbonate derivative is carried out with phosgene, followed by reduction of the 13-keto group to hydroxy group and removal of the protecting groups from the 7- and 10-positions, to obtain 10-deacetyl-14β-hydroxybaccatin III-1,14 carbonate, which is selectively acetylated at the 10-hydroxy group, converted into the 7-triethylsilyl derivative and reacted with (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylic acid. Removal of the triethylsilyl and dimethoxybenzylidene protecting groups affords compound (I).
WO 01/02407 discloses two synthetic routes to compound (I), both starting from 14β-hydroxy-10-deacetylbaccatin III, a constituent of Taxus wallichiana leaves. The first, referred to as process (A), comprises the following steps:                (a) conversion of 14β-hydroxy-10-deacetylbaccatin III into the 7-triethylsilyl derivative;        (b) carbonation of the 1,14 hydroxy groups;        (c) acetylation of the 10-hydroxy group;        (d) reaction of the product of step (c) with (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylic acid;        (e) cleavage of the triethylsilyl and dimethoxybenzylidene groups from the product of step (d);        
The second one, referred to as process (B), comprises the following steps:                (a′) acetylation of the 10-hydroxy group of 14β-hydroxy-10-deacetylbaccatin III;        (b′) carbonation of the 1,14 hydroxy groups;        (c′) silylation of the 7-hydroxy group;        (d′) reaction of the product from step (c′) with (4S,5R)-N-Boc-2-(2,4-dimethoxyphenyl)-4-isobutyl-1-oxazolidine-5-carboxylic acid;        (e′) cleavage of the triethylsilyl and dimethoxybenzylidene groups from the product of step (d′).        
In process B, carrying out acetylation of the 10-hydroxy group before protecting the 7-position allows to avoid the formation of a mixture of regioisomers at the 7- and 10-positions, which always occurs in process A, where acetylation is carried out after protection of the 7-hydroxy group. Therefore, process B is advantageous over process A in that it is highly regioselective. However, scaling up process B to a multi-kilo scale is troublesome, because, for the sake of safety, large amounts of phosgene cannot be loaded into a reactor, thus step (b′) cannot be carried out by adding 14β-hydroxy-10-deacetylbaccatin III to phosgene. If phosgene is instead bubbled into a solution of 14β-hydroxy-10-deacetylbaccatin III, a relevant amount (about 7%) of impurity (II) forms.

Formation of (II) is due to the fact that also the 7-hydroxy group is reactive to phosgene, giving rise to compound (III).

Thus, when carbonation is carried out on a large scale and phosgene is bubbled into the reactor, compound (III) reacts with 14β-hydroxy-10-deacetyl baccatin III, leading to (II).
This impurity also forms when process (B) is carried out on a smaller scale, but in amounts lower than 0.4%.
Due to the close structure similarity with 14β-hydroxybaccatin III-1,14 carbonate, compound (II) can be removed only through column chromatography, thus lowering the yield and increasing the cost of the process, especially on an industrial scale.
A further drawback of process B lies in the fact that triethylsilyl fluoride which forms after removal of the TES group cannot be completely removed by crystallisation and low-pressure column chromatography is necessary to obtain a final product complying with the purity requirements of pharmaceutical products. However, it is well known that on an industrial scale low-pressure column chromatography is troublesome, expensive and poses problems with the handling and destruction of silica contaminated with toxic materials.